Preparation of 2-methyl-4-isopropylidene-5(4)-oxazolone



Patented Feb. 7, 1950 John C. Sheehan, Arlington Heights, Mass, and Ralph Mozingo, Elizabeth, Karl Folkers, Plainfield, and Max Tishler, Rahway, N. J assignors to Merck & 00., Inc.; Rahway, N. J., a corporation of New Jersey No Drawing. Original application March 22,

1946, Serial N0. 656,512. Divided and this application lYlay 4, 1948, Serial No. 25,094

2 Claims. (Cl. 260307) This application is a division of our pending application, Serial No. 656,512, filed March 22, 1946.

This invention relates to the preparation of d1- penicillamine and related compounds which are useful as intermediates in the synthesis of penicillin and chemically related substances having antibiotic activity, and particularly to processes for preparing such compounds from new intermediates obtained from readily available starting materials such as dl-valine and dimethylacrylic acid.

d-Penicillamine has been prepared from pent-'- cillin by hydrolyzing a salt of penicillin with hot dilute mineral acid (Nature 151, 107 (January 23, 1943)). It has been determined that the product thus obtained is an a-amino acid of the d or,

unnatural series having a structure fullydefined by the chemical names d-oc -amino-c-mer captoisovaleric acid or d-fl,B-dimethyl cysteine.

It is now discovered, in accordance with the present invention, that penicillamine can be prepared readily and in good yield from certain new intermediate compounds such as 2-alkyl- 4-isopropylidene-5 (4) -oxazolones, their and esters thereof, by reacting such a compound with absolute methanol saturated with hydrogen sulfide, and preferably containing dissolved sodium methoxide, neutralizing the reaction mixture With anhydrous mineral acid, removing the solvent under reduced pressure, hydrating the 2- alkyl-5,5-dimethyl-A -4-thiazoline carboxylic acid or ester thus formed to N-acyl-dl-pencillamine or an ester thereof, and converting the same to a dl-pcnicillamine hydrohalide and to free dl-penicillamine by reacting with aqueous hydrohalic acid and then reacting the hydrohalide, under anhydrous conditions, with pyridine.

The starting materials can be prepared from dl-valine by converting the same to an N-ahaloacyl derivative, forming a salt or addition compound of the N-a-haloacyl derivative with a nitrogenous heterocyclic compound having a pyridine nucleus, and converting the same to a 2-alkyl-4-isopropylidene-5 (4) -oxazolone or to hydration products such as u-acylamino-B,c-dihydration products a-acylamino-/3,,8-dimethylacrylic acids,

methylacrylic acid and esters thereof in accord-' ance with a procedure fully disclosed in a copending joint application of two of the present and then with aqueous ammonium hydroxide to form n amino-,B-methoxyisovaleric acid, reacting the same with an acyl anhydride to form a-acylamino-lm-dimethylacrylic acid, is disclosed in a co-pending joint application of two of the present applicants, Mozingo and Folkers, Serial No. 656,510, filed March 22, 1946, now U. 8. Patent 2,460,708.

It is also discovered, in accordance with the present invention that 2-methyl-4-isopropylidene-5(4) -oxazo1one can be prepared by reacting a-amino-fi-methoxyisovaleric acid with acetic anhydride and triethyl amine and removing solvents from the reaction mixture under reduced pressure as more fully hereinafter disclosed.

In carrying out the process of the present invention, a 2-alkyl-4-isopropylidene-5(4) -oxazolone or a corresponding hydration product, prepared by any of the procedures outlined above, is dissolved in absolute methanol and added sloW- ly to absolute methanol saturated at about 0 C. with hydrogen sulfide. It is also advantageous, though not absolutely necessary, that the methanol-hydrogen sulfide solution contain dissolved sodium ,methoxide. During the addition, which takes about one to one and one-half hours, and for about sixteen hours thereafter hydrogen sulfide is passed through the reaction mixture and the temperature is gradually increased to about room temperature. The reaction. mixture is then neutralized with anhydrous methanolic hydrogen chloride and the solvent is removed by heating (to about 40 C.) under reduced pressure, yielding a crude 2-alky1-5,5-dimethyl-A -4-thiazolinecarboxylic acid or ester thereof.

This can be purified by dissolving in ether and quickly filtering to remove sodium chloride. Upon standing, the product crystallizes from the ether filtrate and can be further purified by recrystallization from benzene. The thiazoline is quantitatively converted to N-acyl-d1-penicillamine by warmingwith water.

In carrying out the process to prepare dl-penicillamine and related compounds, it is not necessary to isolate the thiazoline compound. The crude mixture obtained after neutralization and evaporation of solvent as above described can be merely warmed with water and chilled to cause crystallization of the N-acyl-dl-pencillamine, which is recovered by filtration. The N-aoyl-dlpencillamine is purified by recrystallization from hot water.

N-acyl-dl-penicillamine is converted to dl-penicillamine, preferabl through a hydrohalide of dl-peni'cillamine, by reacting with an aqueous hydrohalic acid in an oxygen-free (nitrogen) atmosphere, as by refluxing with hydrochloric acid for about sixteen hours, concentrating and drying the reaction mixture, and crystallizing the dipenicillamine hydrohalide by trituration with dry ether. When the hydrohalide is dissolved in absolute methanol, treated with pyridine, and the reaction mixture is then cooled to 'about' C., dl-penicillamine crystallizes out and is recovered by filtration.

The following is a graphic representation of" the procedure above described using'as a'sta'rting material 2-methyl 4 isopropylidene-5(4)- oxazolone:

captoisovaleric acid (N -acctybdl-pcnicillamine) Aqueous hydrochloric acid C33 /0 CH; O

d i I pyri inc /SH N112 OH [SH NH: OH CH; anhydrous C 3' HO] conditions dl-a-Ainiiio-d-inercaptoisovaleric acid d1-a-Amino-B-inercapto- (dl-penicillamine) isovaleri'c acid hydrochloride (dl-pcnicillamine hydrochloride) The following examples illustrate methods of carrying out the present invention, but it will' be understood that these examples are given byway of illustration and not of limitation;

Example I A mixture of 73.5 g. of a-fillliIlO-fi-HlthOXYiSO- valeric acid, 180 ml. of acetic anhydride, an'dl ml. of triethylamine was warmed on a steam- After removal of solbath for one-half hour; vents under reduced pressure, the residue crystallized as crude 2-methyl-4 isopropylidefie- 5(4) -0xazolone. The product is suitable for use without further purification. Upon recrystallization from 30-60 petroleum ether, 63.5 g. (94%) of the azlactone was recovered having 'a' melting point of 37-38 C. A sample was evapo ratively distilled at 70 and 0.01 mm. and'a'nalyzed immediately.

Calculated for C7H902NI c, 60.42; H, 6.52. Found: C, 60.34; H, 6.21.

Example II A solution of 0.6 g. of sodium in 100 ml. of

absolute methanol was saturated at 0 with hydrogen sulfide. solution of 2-methyl-4-isopropylidene-5(4) -oxazolone in 40 ml. of methanol was added. During the addition and for sixteen hours there-'- after, a stream of hydrogen sulfide was allowed- Over a period of one 'hour, a

4 to pass through the solution, the temperature being gradually increased to 25.

After neutralization with 2.2 ml. of methanol containing 048g. of dry hydrogen chloride per ml'., the solvent was removed (40) under reduced pressure. The residual amber syrup was dissolved in dry ether and quickly filtered from sodium chloride. The filtrate soon crystallized, yielding 7.2 g. of colorless needles, M. P. 126-130. By recrystallization from benzene the melting point was raised to 130-132. This product, 2,5,5- triinethyl A -i-thiazolinecarboxylic acid, contains sulfur, gives a negative ferric chloride test for the sulihydryl group, and dissolves in a sodium bicarbonate solution with eifervescence.

Analysis:

Calculated for C7H1102NSI C, 48.53; H, 6.40;

N, 8.07. Found: C, 48.81; H, 6.10; N, 7.91.

This thiazoline is rapidly and quantitatively converted to N-acetyl-dl-penicillamine by warming in water for several minutes.

Example III A solution of the crude azlactone, prepared from73.5 g. of a-amino-;8-methoxyisovaleric acid as-in' Example I, in ml. of methanol was added in one and one-half hours to a solution of 1.77 g.'of* sodium in 292 ml. of methanol saturated with hydrogen sulfide at 0. A stream of hydrogen sulfide was allowed to pass through the solution during the addition and for sixteen hours thereafter, the temperature gradually being increased to 25. After neutralization with 6.3 ml. of methanol containing 0.43 g. of hydrogen chloride per ml., the solvent was removed under reduced pressure. The amber syrup was warmed with 200 ml. of water for ten minutes, then chilled and filtered, yielding 75.5 g. (80% overall) of N-acetyl penicillamine; M. P. 175-177 (dec.).

This product, when recrystallized from hot water, was recovered as glistening colorless needles melting at 183 C.

Analysis:

Calculated for C7H13O3NS: C, 43.91; H, 6.55;

N, 7.33. Found: C, 43.97; H, 6.98; N, 7.06.

Example IV A' mixture of 20 g. of recrystallized N-acetyl penicillamine, 210 ml. of 2.5 N hydrochloric acid and ml. of water was refluxed sixteen hours under nitrogen. A trace of hydrogen sulfide was evolved. After concentration under reduced pressure, the syrup was dried by flushing twice with absolute alcohol and once with benzene under reduced pressure. The residue crystallized readily on trituration with dry ether, yielding 19.6 g. (100%) of dl-penicillamine hydrochloride; M. P. -148 (dec.) The purity as determined by iodine titration was 96-98%.

Example V A solution of the aforementioned pencillamine hydrochloride (18.6 g.) in 28 ml. of absolute alcohol was clarified by centrifuging. After the addition of 15 ml. of pyridine and cooling to 0, dl-pencillamine was filtered off, weight 9.70 g. (65%); M. P. 20l-202 (dec.), undepressed with authentic pencillamine. The filtrate was c0ncentrated to a syrup, dissolved in 15 ml. of water and made alkaline with 30% sodium hydroxide. Afterconcentration under reduced pressure, the lasttraces of pyridine were removed with ether.

The mixture was acidified with hydrochloric acid, concentrated to dryness, flushed with absolute alcohol and dissolved in absolute alcohol. Subsequent removal of sodium chloride and neutralization as before with pyridine afforded an additional 1.66 g. of pencillamine; M. P. 201 (dec.). The total yield overall from N-acetyl penicillamine was 77%.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and our invention is to be limited only by the appended claims.

We claim:

1. The process that comprises heating a mixture of a-amino-p-methoxyisovaleric acid, acetic anhydride, and triethylamine, for about onehalf hour, and evaporating volatile components from the reaction mixture under reduced pressure to crystallize 2-methyl-4-isopropylidene- 5 (4) -oxazolone.

2. The process that comprises heating a mixture of a-amino-B-methoxyisovaleric acid, acetic anhydride, and triethylamine at about 100 C.,

JOHN C. SHEEHAN. RALPH MOZINGO. KARL FOLKERS. MAX TISHLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 743,986 Nicolaier et al. Nov. 10, 1903 2,391,993 Mathes Jan. 1, 1946 OTHER REFERENCES Organic Reactions, vol. 111, page 211 and footnote. pp. 200, 201, and 202 (1946), Adams et al., John Wiley and Sons, Inc., New York. 

1. THE PROCESS THAT COMPRISES HEATING A MIXTURE OF A-AMINO-B-METHOXYISOVALERIC ACID, ACETIC ANHYDRIDE, AND TRIETHYLAMINE, FOR ABOUT ONEHALF HOUR, AND EVAPORATING VOLATILE COMPONENTS FROM THE REACTION MIXTURE UNDER REDUCED PRESURE TO CRYSTALLIZE 2-METHYL-4-ISOPROPYLIDENE5(4) -OXAZOLONE. 